What is ABT-737?

Acalabrutinib (ACP-196) is a selective second-generation BTK inhibitor that inhibits the activation of the B cell surface proantibody signaling pathway. It has good target specificity, with a selectivity of 323-, 94-, 19-, 9-fold higher for BTK than other members of the TEC kinase family such as ITK, TXK, BMK, and TEC. No activity on EGFR.

Basic Information

Product Name: Acalabrutinib; ACP-196

CAS:1420477-60-6

MF:C26H23N7O2

MW:465.51

EINECS:814-272-0

MDL No.:MFCD29472294

Appearance: Yellow powder

Purity: 98%+

Package: 10g; 100g ;1kg

MOQ: 1g

Origin: China

Used: lab research

Stability: Stable

Delivery Time: 3-7days

Structural formula:

Technical Specification:

What is the function of ACP-196?

ACP-196 is an experimental anti-cancer drug and a selective Bruton tyrosine kinase (BTK) inhibitor. This kinase transmits signals from the B cell receptor (BCR), so any genetic BTK mutation can lead to B cell immune deficiency.

Acalabrutinib is an experimental anti-cancer drug and a selective inhibitor of Bruton tyrosine kinase (BTK). This kinase transmits signals from the b cell receptor (BCR), so any BTK gene mutation can lead to b cell immune deficiency.

Mechanism of action

Acatinib is a second-generation small molecule Bruton tyrosine kinase inhibitor. Acatinib and its metabolite ACP-5862 form a covalent binding with the 481st cysteine residue of the BTK active site, which inhibits the activity of BTK enzyme; And BTK serves as a signaling pathway for B cell antigen receptors and cytokine receptor channels, which are chemically regulated. In B cells, the activation of BTK signaling is a necessary channel signal for promoting B cell proliferation, transport, chemotaxis, and adhesion. Acatinib and its metabolites selectively block the BTK pathway without disrupting other molecular pathways important for platelet and immune function, thereby avoiding or reducing the occurrence of cancer treatment-related adverse reactions.

Biological activity

In vitro: Acalabrutinib inhibits ERK, I in vitro signaling assays of primary human CLL cells κ Tyrosine phosphorylation of downstream targets of B and AKT.

In vivo: In a human CLLNSG xenograft model, it showed targeted effects, including PLC γ 2. Reduced phosphorylation of ERK and significant inhibition of CLL cell proliferation. It significantly reduces tumor burden in the spleen of mice with . In the TCL1 adoption transfer model, it treatment reduces BTK and PLC γ Phosphorylation of 2 and S6. Most notably, compared to mice receiving the vector, acalabrutinib significantly increased survival rate. It (100mg twice a day) evaluated thrombosis in damaged small arteries of mice and showed stronger selectivity in inhibiting BTK, with almost no inhibition of platelet activity.

Solubility

In vitro research

In vitro signal detection of primary human chronic lymphocytic leukemia cells, it inhibits tyrosine phosphorylation of downstream targets ERK, IKB, and AKT. Among the 9 kinases located in the same position as BTK cysteine, it exhibits higher selectivity towards BTK than towards other kinases. It does not inhibit EGFR, ITK, and TEC, and has no effect on the phosphorylation of EGFR at Y1068 and Y1173 sites. Compared to ibrutinib, it has a higher IC50 value and almost no inhibitory effect on the kinase activity of ITK, EGFR, ERBB2, ERBB4, JAK3, BLK, FGR, FYN, HCK, LCK, LYN, SRC, and YES1.

In vivo research

Oral treatment of ACP-196 in mice inhibited anti-IgM induced CD86 expression in CD19+splenocytes in a dose-dependent manner, with an ED50 of 0.34 mg/kg. After 3 hours of treatment, inhibited>90% of CD86 expression levels

Synthesis Process：

A solution containing N - (pyridine-3-ylbenzamide (S) -4- (8-amino-3- (pyrroline-2-) imidazolo [1,5-a] pyrazine) - N - [pyridin-2-yl] pyridin-2-yl) benzamide (intermediate 2b, 19.7mg, 0.049mmol 9 mmol) was added to dichloromethane (2mL) with triethylamine (20mg, 0.197mmol, 0.027mL) and (E) -4- (pyrroline-1-yl) butyl-2-enoic acid hydrochloride (9.45mg, 0.049mmol). Stir the mixture at room temperature for 30 minutes. Wash the mixture with water, dry with magnesium sulfate and concentrate under vacuum. The residue was purified from Chemicalbook by preparative HPLC. Collect the fraction containing the product and dry it to obtain (S, E) -4- (8-amino-3- (1- (4- (pyrroline-1-yl) butan-2-enyl) pyrroline-2-yl) imidazolino [1,5-a] pyrazine-1-yl) - N - (pyridin-2-yl) benzamide. (S) -4- (8-amino-3- (1-buty-2-alkynylpyrrolidin-2-yl) imidazolo [1,5-a] pyrazine-1-yl) - N - (pyridine-2-yl) benzamide was prepared from the compound described in intermediate 2b and 2-butyric acid in a similar manner as described in Example 2, resulting in the title compound acatinib (10.5mg, 18.0%). M/z466.1 (m+H)+.

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